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Biomedical subjects

R D Clark

Publications and source records attributed to R D Clark.

At least 73 records · Page 4Linked to original sources
PubMed1987

Antihypertensive 1-acyl-4-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethylamino]pip eridines.

Several 1-acyl-4-[2-(1,4-benzodioxan-2-yl)-2-hydroxy-ethylamino]piperidine s were prepared and a number of the compounds showed antihypertensive activity in the spontaneously hypertensive rat (SHR). This activity was specific for the (2S, 2R) enantiomers. General pharmacological evaluation and ligand binding data on selected compounds indicated a moderate degree of alpha 1- and beta-antagonistic activity. The alpha 1 antagonism was probably not of sufficient magnitude to explain the blood pressure lowering activity in the SHR.

Animals↗
PubMed1987

Synthesis and pharmacological evaluation of N,N-di-n-propyldopamine congeners containing phenolic bioisosteres.

A series of analogues of N,N-di-n-propyldopamine (DPDA) in which the 3-hydroxyl group was replaced by bioisosteric groups was prepared and evaluated for D1- and D2-receptor affinity. The 3-methane-sulfonamide analogue (18) had a higher affinity for the D2 receptor than DPDA and was more selective for the D2 receptor. The 3-formamide derivative (15) also retained significant D2 affinity. Both of these compounds demonstrated in vivo cardiovascular and renal profiles in an anesthetized rat model that were consistent with selective D2-receptor agonism.

Animals↗
PubMed1987

Discriminative stimulus properties of ethosuximide in the pigeon.

After initial exposure to 80 mg/kg, pigeons trained on a two-key drug discrimination procedure rapidly learned to discriminate 120 mg/kg ethosuximide from saline. When 40-160 mg/kg doses of ethosuximide were administered during generalization tests, the percentage of responses directed to the ethosuximide-appropriate key varied directly with dose. Time-effect determinations revealed that the discriminable properties of ethosuximide were evident as early as 15 min after, and as late as 2 h after, intramuscular injection. The discriminative stimulus properties of ethosuximide failed to generalize to the anticonvulsant compounds clonazepam (0.5-4 mg/kg), methsuximide (25-200 mg/kg), and phenytoin (5-15 mg/kg). Generalization was apparent with certain doses of primidone (250, 300 mg/kg) and mephenytoin (80, 160, 240 mg/kg). The concomitant administration of pentylenetetrazol (5, 10, 20 mg/kg) partially blocked the discriminable properties of the training dose of ethosuximide.

Animals↗
PubMed1986

Antihypertensive aminotetralins related to labetalol and medroxalol.

A series of compounds was prepared in which the 1-methyl-3-phenylpropylamino moieties of the antihypertensive agents labetalol and medroxalol were replaced by 2-aminotetralins. Compounds containing a 6-methoxy and 6,7-methylenedioxy group in the aminotetralin were at least as active as labetalol in lowering the blood pressure of the spontaneously hypertensive rat (SHR). As determined by ligand binding, these compounds were comparable to labetalol as alpha 1-antagonists but were substantially weaker beta 1-antagonists.

Animals↗
PubMed1985

Ultrastructural correlates of transmitter release in presynaptic areas of lamprey reticulospinal axons.

The ultrastructure of presynaptic areas of lamprey reticulospinal axons was studied before, during, and after periods of elevated transmitter release produced either by repetitive action potential activity or depolarization by elevated extracellular potassium. Controls for possible effects of these procedures per se were done by replacing extracellular Ca with Mg to block transmitter release. In some experiments the time course of ultrastructural changes during K depolarization and subsequent recovery were studied by fixing tissue samples at various times. Transmitter release produced by action potential activity (20/sec for 15 min) in the presence of extracellular Ca significantly and reversibly decreased the number of synaptic vesicles, the area occupied by the vesicles, and the density of synaptic vesicles. An unexpected finding was a reversible decrease in the length of the differentiated membrane during periods of increased transmitter release. Transmitter release significantly and reversibly increased the number of coated vesicles, expanded the presynaptic membrane, and increased the number of pleomorphic vesicles. K depolarization (50 mM K for 15 min) produced identical, reversible effects, except that the expansion of the presynaptic membrane, although significant, was relatively small and there was no change in the number of pleomorphic vesicles. Raising the temperature of the saline from 2 degrees C (K depolarization experiments) or 7 degrees C (action potential experiments) to 20 degrees C did not change the results qualitatively but did produce somewhat larger effects during stimulation and appeared to increase the speed of recovery. Action potential activity or K depolarization in control experiments with the Ca in the saline replaced by Mg had little or no effect on synaptic ultrastructure. Synaptic vesicles in lamprey reticulospinal axons never contacted the axonal membrane anywhere other than at the differentiated membrane. During periods of elevated transmitter release, although the absolute number of vesicles in contact with the differentiated membrane decreased, the percentage of total vesicles in contact with the differentiated membrane increased dramatically. This suggests that the differentiated membrane is the site of vesicle release and there is an active process of vesicle movement to this membrane. In the course of this work it was observed that presynaptic areas closer than approximately 2 mm to the site of axonal transection, regardless of the composition of the saline or the experimental conditions, showed ultrastructural changes typical of increased transmitter release.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1985

Stereoselective behavioral effects of N-allylnormetazocine in pigeons and squirrel monkeys.

The behavioral effects of the stereoisomers of N-allylnormetazocine (NANM) were compared with those of phencyclidine (PCP) in pigeons and squirrel monkeys responding under a multiple fixed-interval fixed-ratio (FI FR) schedule of food presentation. Intermediate doses of (+)-NANM or PCP produced transient increases in FI responding in monkeys and sustained increases in FI responding in pigeons; higher doses decreased FI and FR responding in both species. In contrast to its enantiomer, (-)-NANM failed to increase FI responding significantly in either species; at high doses, (-)-NANM decreased FI and FR responding. In monkeys, (-)-NANM was about 10 times more potent than (+)-NANM in decreasing responding, whereas in pigeons (-)-NANM was about equipotent with (+)-NANM. In both species, (-)-NANM, but not (+)-NANM, antagonized the rate-decreasing effects of morphine on FI and FR responding. In monkeys, the effects of (-)-NANM, but not (+)-NANM or PCP, were antagonized by naloxone; the doses of naloxone required to antagonize the effects of (-)-NANM were more than 100 times higher than those required to antagonize the effects of morphine. In pigeons, naloxone did not systematically alter the effects of (-)-NANM, (+)-NANM or PCP. Haloperidol reduced or eliminated the increases in FI responding produced by intermediate doses of either (+)-NANM or PCP in pigeons, but did not antagonize the decreases in FI or FR responding produced by high doses of PCP or either stereoisomer of NANM. The results demonstrate a high degree of stereoselectivity in the behavioral effects of NANM. The levorotatory isomer had opioid-antagonist and non-opioid agonist effects in pigeons and mixed opioid agonist-antagonist effects in monkeys. The dextrorotatory isomer, on the other hand, had effects similar to those of PCP in both species.

Animals↗
PubMed1984

Peritonitis prevented in continuous ambulatory peritoneal dialysis by using the Hong Kong connection.

Based on the hypothesis that air contamination is an important cause of peritonitis in continuous ambulatory peritoneal dialysis, a simple and cheap connection system was developed whereby a clear polyethylene bag containing an antiseptic gauze was used as a sterilising chamber, effectively enclosing the connection procedure. Seven modifications to the connection technique were introduced over 32 months in 28 patients during 27.9 patient years of experience. The overall rate of peritonitis was 0.6 episode/patient year, but after a final modification at the beginning of the third year the rate fell to 0.17, without a single case of peritonitis occurring attributable to a connection failure in 11.5 patient years. These findings show that in patients receiving continuous ambulatory peritoneal dialysis peritonitis may be prevented by enclosing the connection process and sterilising the introduced air and tubing ends.

Air↗
PubMed1984

Determinants of prognosis of patients with aortic regurgitation who undergo aortic valve replacement.

Insidious and potentially irreversible left ventricular dysfunction may develop in patients with aortic regurgitation. To determine whether preoperative variables can predict postoperative outcome, 113 consecutive patients with aortic regurgitation who underwent surgical correction between 1962 and 1977 were studied and survivors were followed up for 4.6 +/- 3.3 years. Clinical and hemodynamic examinations were made in all patients before the operation. Echocardiograms were performed in 44 patients preoperatively and in 36 patients postoperatively. Perioperative or postoperative death due to congestive heart failure occurred in only eight patients (19%). No statistically significant predictors of total mortality or death due to cardiac failure were found based on preoperative clinical, hemodynamic or echocardiographic findings. Survivors of the operation showed significant functional improvement: preoperatively, 77% of all patients were in functional class III or IV; postoperatively, 84% of patients were in class I or II (p less than 0.0001). A weak statistical correlation of functional improvement was found with a preoperative presence of increased cardiac diameter on the chest radiograph (p less than 0.05) and the severity of left ventricular hypertrophy (p less than 0.05). Improvement of left ventricular function was also consistently found in survivors and correlated best with the degree of preoperative preservation of left ventricular function. Patients with an echocardiographic preoperative fractional shortening of the minor diameter greater than 26%, end-systolic dimension less than 55 mm and end-diastolic dimension less than 80 mm were most likely to have normal function after the operation. It is concluded that operative mortality and survival after surgical correction of aortic regurgitation cannot be accurately predicted from preoperative findings.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1983

Isolation of a five-polypeptide cytochrome b-f complex from spinach chloroplasts.

A simple rapid purification of a cytochrome b-f complex from spinach chloroplasts is described. Novel features of the method include: 1) EDTA treatment of thylakoids prior to detergent extraction; 2) affinity chromatography over equine cytochrome c linked to Sepharose 4B; and 3) inclusion of the protease inhibitor phenylmethylsulfonyl fluoride. Cytochrome b-f complex is obtained in good yield, free of exogenous lipid, and with high plastoquinol:plastocyanin oxidoreductase activity. The complex contains 2 eq of cytochrome b-563 per eq of cytochrome f and a Rieske iron-sulfur center. Polyacrylamide gel electrophoresis in the presence of dodecyl sulfate indicates that the complex is composed of five distinct polypeptides of Mr = 37,000, 33,500, 22,000, 19,000, and 16,500. Only the Mr = 33,500 and 22,000 polypeptides stain for heme. The Mr = 37,000 component in this preparation is absent from cytochrome b-f complex isolated by another procedure (Hurt, E., and Hauska, G. (1981) Eur. J. Biochem. 117, 591-599). The complex described here also differs in its spectrum at 77 K, its stability, and its buoyant density.

Centrifugation, Density Gradient↗
PubMed1983

Spontaneous carotid-cavernous fistula and the Ehlers-Danlos syndromes.

A 22-year-old woman with one of the Ehlers-Danlos syndromes (EDS) developed a spontaneous carotid-cavernous fistula (CCF), demonstrated by ophthalmic ultrasound and cerebral angiography. Therapy consisted of two balloon embolization procedures that significantly reduced blood flow through the fistula. The patient subsequently had a cerebral hemorrhage and expired. The cardinal features of EDS and its ophthalmologic findings are reviewed. Spontaneous CCF have been described in EDS patients, but case documentation is lacking in the ophthalmic literature. The rationale for treating a CCF and the various therapeutic approaches are discussed; the serious risks involved in any attempt to save vision in these patients are considered.

Adult↗
PubMed1983

Synthesis and antihypertensive activity of 4'-substituted spiro[4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-ones.

A series of 4'-substituted spiro[4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-ones was prepared and evaluated for antihypertensive activity in the spontaneously hypertensive rat (SHR). The basic ring system was prepared in one step by condensation of dilithiated (tert-butoxycarbonyl)aniline (3) with (tert-butoxycarbonyl)piperidinone. Deprotection afforded 6, which was condensed with expoxides or alkyl halides to furnish the title compounds. The most active compound was dl-erythro-4'-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]spiro [4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-one (9), and various modifications of this compound were made in order to elucidate the structure-activity relationships in the series. Preliminary indications are that 9 may act by both central and peripheral mechanisms.

Animals↗
PubMed1983

Antihypertensive 9-substituted 1-oxa-4,9-diazaspiro[5.5]undecan-3-ones.

Forty-one 9-substituted 1-oxa-4,9-diazaspiro[5.5]undecan-3-ones were prepared for antihypertensive screening in the spontaneously hypertensive rat (SHR). For the 9-(2-indol-3-ylethyl) series, the parent compound, 9-(2-indol-3-ylethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one (21), was the most potent antihypertensive agent. Substitution of lower alkyl groups on the spirolactam ring gave compounds close in activity to 21, while substitution with large alkyl or aryl groups led to a significant decrease in activity. Ring-opened analogues of 21 that contained the same functionality were markedly less active. Several 1-oxa-4,9-diazaspiro[5.5]undecan-3-ones substituted at the 9 position with 1,4-benzodioxan-2-ylmethyl, 1,4-benzodioxan-2-ylhydroxyethyl, and 2-phenylethyl groups also demonstrated significant activity. Compound 21 was chosen for a detailed pharmacological evaluation. Its antihypertensive activity appears to be predominantly due to peripheral alpha 1-adrenoceptor blockade.

Adrenergic alpha-Antagonists↗
PubMed1983

Synthesis and antihypertensive activity of a series of spiro[1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizine-2,5'-oxazolidin-2'-one]s.

The 2R*,11bS* and 2S*,11bS* diastereoisomers of the spiro[1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizine-2, 5'-oxazolidin-2'-one] system were prepared by stereoselective methods. Evaluation of these compounds for antihypertensive activity by oral administration to the spontaneously hypertensive rat showed the 2S*,11bS* series was the more potent. Within that series it was found that small alkyl substituents at positions 3 and 4' enhanced antihypertensive activity and that methoxyl substitution at positions 9 and 10 was optimal. (2S,3S,11bS)-Spiro-[2-ethyl-9,10-dimethoxy-1,3,4,6,7, 11b-hexahydro-2H-benzo[a]quinolizine-2,5'-oxazolidin-2'-one] [(-)-9e] was one of the most efficacious compounds of this series, while its antipode, (+)-9e, was inactive. Selected compounds in this series were shown to be alpha-adrenoceptor antagonists.

2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-↗